CNS Pathways Regulating Ghrelin Effects on Body Weight

描述（由申请人提供）：肥胖发病率的上升是美国面临的主要健康问题。幸运的是，在过去的十年中，已经确定了控制体重和葡萄糖稳态的几个关键激素和中枢神经系统（CNS）途径。事实上，我们现在有了一个粗略的中枢神经系统路线图，通过它，像胃饥饿素这样的关键代谢信号发挥其作用，可能会导致有效的策略来对抗肥胖、糖尿病和饮食失调的发病率。在过去的资助期内，我们试图描述胃饥饿素及其受体，生长激素分泌ouge受体（GHSR；胃饥饿素受体）选择性调节食物摄入和体重的神经基质。我们创造了一种新的GHSR缺失小鼠，发现缺乏ghrelin信号可以保护小鼠免受饮食引起的肥胖和糖尿病的影响。在目前的建议中，我们将使用我们的新型小鼠模型来扩展这些观察结果，我们可以在选定的细胞类型中选择性地重新激活GHSR表达。我们将确定结节神经节中的迷走感觉神经元是否足以恢复其他地方缺乏GHSRs的小鼠胃饥饿素的厌氧特性。接下来，我们将确定脑干中关键自主调节神经元的GHSR重新表达是否需要正常体重和葡萄糖稳态。最后，我们还将确定胰腺中2个细胞中GHSRs的重新激活是否足以恢复饥饿素在面对饮食引起的肥胖时抑制胰岛素水平的能力。公共卫生相关性：本研究提出的实验旨在研究胃饥饿素在调节食物摄入、体重和葡萄糖稳态中的作用。希望这些研究能带来新的靶向疗法来治疗情绪肥胖、糖尿病和饮食失调，如神经性厌食症和神经性贪食症。

DESCRIPTION (provided by applicant): The increasing incidence of obesity is a major health issue facing the USA. Fortunately, in the past decade several key hormones and central nervous system (CNS) pathways controlling body weight and glucose homeostasis have been identified. Indeed, we now have a rough CNS roadmap through which key metabolic signals like ghrelin exert its effects which may lead to effective strategies to combat the incidence of obesity, diabetes and eating disorders. In the past grant period, we sought to delineate the neural substrates through which ghrelin and its receptor, the growth hormone secretagouge receptor (GHSR; ghrelin receptor) selectively regulate food intake and body weight. We created a novel GHSR null mouse and found that lack of ghrelin signaling protected mice from developing diet-induced obesity and diabetes. In the current proposal, we will extend these observations using our novel mouse model in which we can selectively reactivate GHSR expression in selected cell types. We will identify if vagal sensory neurons in the nodose ganglia are sufficient to restore the orexigenic properties of ghrelin in mice lacking GHSRs everywhere else. We will next determine is GHSR re-expression by key autonomic regulatory neurons in the brainstem is required for normal body weight and glucose homeostasis. Finally, we will also determine if reactivation of GHSRs in 2 cells in the pancreas is sufficient to restore the ability of ghrelin to suppress insulin levels in the face of diet induced obesity. PUBLIC HEALTH RELEVANCE: The experiments proposed in this study have been designed to investigate the role ghrelin plays in regulating food intake, body weight and glucose homeostasis. It is hoped that these studies will result in new targeted therapies to treat mood obesity, diabetes and eating disorders such as anorexia nervosa and bulimia nervosa.